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dc.contributor.authorCoelho, Paula Aen
dc.contributor.authorBury, Leahen
dc.contributor.authorShahbazi, Marta Nen
dc.contributor.authorLiakath-Ali, Kifayathullahen
dc.contributor.authorTate, Peri Hen
dc.contributor.authorWormald, Samen
dc.contributor.authorHindley, Christopheren
dc.contributor.authorHuch Ortega, Meritxellen
dc.contributor.authorArcher, Joyen
dc.contributor.authorSkarnes, William Cen
dc.contributor.authorZernicka-Goetz, Magdalenaen
dc.contributor.authorGlover, Daviden
dc.date.accessioned2019-04-15T23:30:34Z
dc.date.available2019-04-15T23:30:34Z
dc.date.issued2015-12en
dc.identifier.issn2046-2441
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/291634
dc.description.abstractTo address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of tumour formation that occurs in the absence of the tumour suppressor p53. Plk4 over-expression also leads to hyperproliferation of cells in the pancreas and skin that is enhanced in a p53 null background. Pancreatic islets become enlarged following Plk4 over-expression as a result of equal expansion of α- and β-cells, which exhibit centrosome amplification. Mice overexpressing Plk4 develop grey hair due to a loss of differentiated melanocytes and bald patches of skin associated with a thickening of the epidermis. This reflects an increase in proliferating cells expressing keratin 5 in the basal epidermal layer and the expansion of these cells into suprabasal layers. Such cells also express keratin 6, a marker for hyperplasia. This is paralleled by a decreased expression of later differentiation markers, involucrin, filaggrin and loricrin. Proliferating cells showed an increase in centrosome number and a loss of primary cilia, events that were mirrored in primary cultures of keratinocytes established from these animals. We discuss how repeated duplication of centrioles appears to prevent the formation of basal bodies leading to loss of primary cilia, disruption of signalling and thereby aberrant differentiation of cells within the epidermis. The absence of p53 permits cells with increased centrosomes to continue dividing, thus setting up a neoplastic state of error prone mitoses, a prerequisite for cancer development.
dc.format.mediumPrinten
dc.languageengen
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectIslets of Langerhansen
dc.subjectCells, Cultureden
dc.subjectCiliaen
dc.subjectCentrosomeen
dc.subjectCentriolesen
dc.subjectAnimalsen
dc.subjectMiceen
dc.subjectHyperplasiaen
dc.subjectIntermediate Filament Proteinsen
dc.subjectProtein-Serine-Threonine Kinasesen
dc.subjectMembrane Proteinsen
dc.subjectProtein Precursorsen
dc.subjectCell Proliferationen
dc.titleOver-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse.en
dc.typeArticle
prism.issueIdentifier12en
prism.publicationDate2015en
prism.publicationNameOpen biologyen
prism.startingPage150209
prism.volume5en
dc.identifier.doi10.17863/CAM.38792
rioxxterms.versionofrecord10.1098/rsob.150209en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-12en
dc.contributor.orcidLiakath-Ali, Kifayathullah [0000-0001-9047-7424]
dc.contributor.orcidHindley, Christopher [0000-0002-5294-1270]
dc.contributor.orcidHuch, Meritxell [0000-0002-1545-5265]
dc.contributor.orcidZernicka-Goetz, Magdalena [0000-0002-7004-2471]
dc.contributor.orcidGlover, David Moore [0000-0003-0956-0103]
dc.identifier.eissn2046-2441
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (11431)
pubs.funder-project-idCancer Research UK (CRUK-A18795)
pubs.funder-project-idMRC (G1001696)
pubs.funder-project-idWELLCOME TRUST (104151/Z/14/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International